Since 1983, it has been explicated that HIV forms the cause of AIDS (Acquired Immune Deficiency Syndrome) and AIDS-related diseases. At the beginning of its discovery, HIV had been differently named LAV (Lymphoadenopathy Associated Virus) by French researchers, or HTLV-III (Human T-lymphotropic Virus Type III) or ARV (AIDS-Related Virus) by American researchers. However, it was determined in 1986 that the designation of the virus is unified into HIV. WHO predicts that AIDS patients and HIV-infected persons in the world will reach ten millions and forty millions, respectively, by 2000. On the other hand, AIDS patients and HIV-infected persons in Japan are 378 and 1,656, respectively, as of April, 1991, and are increasing surely.
As described above, AIDS now grows into a great foe of the human. However, no basic therapy has been found yet. Only azidothymidine (AZT; 3'-azido-3'-deoxythymidine) has been approved up to the present [Mitsuya, et al.: Proc. Natl. Acad. Sci. U.S.A. 82, 7096-7100 (1985)]. AZT has been confirmed in its effectiveness by what life-prolonging effect is recognized to a significant extent, and so on. On the other hand, it has been said that a myelodepresant effect is remarkably observed as a side effect in addition to headache and gastrointestinal disorders, and long-term administration hence offers a problem [Richmann, D. D. et al.: New Engl. J. Med., 317, 185-197 (1987)]. AZT has also been said that it is of no effect on cells already infected with HIV, and although it can prevent the crisis of AIDS-related complex, it is directly useless for remedy after infection.
In addition to AZT, many anti-HIV agents including nucleic acid derivatives, soluble CD4 and the like have been researched and developed. As literature related to the present invention, there are documents which describe porphyrin or chemically modified plasma proteins as having an anti-HIV activity.
Asanaka et al. have reported that protoporphyrin exhibits an anti-HIV activity in an MT-4/LAV-infected system [AIDS 3, 403-404 (1989)]. However, this mechanism is considered to be the same as the anti-HIV effect of dextran sulfate in which so-called adsorption stage of HIV on MT-4 cells is inhibited.
Levere et al. have proved with human peripheral blood lymphocytes and H9 cells that when AZT and heme are used in combination in an amount of 1-10 .mu.M against AZT-resistant HIV, the replication of HIV can be remarkably inhibited [Proc. Natl. Acad. Sci. U.S.A., 88, 1756-1759 (1991)].
Tsunoo et al. have proved that succinylated or maleylated plasma proteins have an anti-HIV activity (Japanese Patent Application Laid-Open No. 275824/1990).
All the anti-HIV activities of the substances described above are against the infection and proliferation of HIV, and have no killing effect on cells persistently infected with HIV.
It is accordingly an object to provide an anti-HIV agent which has a killing effect on HIV-infected cells and is useful for the prophylaxis and treatment of AIDS.
Thus, the present inventors have synthesized a number of chemically modified porphyrins and screened them from both standpoints of the killing effect on cells persistently infected with HIV and the safety for normal cells. As a result, it has been found that a porphyrin derivative obtained by modifying a porphyrin with a carbodiimide, an alkylenediamine or an alcohol, or a complex of a porphyrin or the porphyrin derivative with a plasma protein or a chemically modified plasma protein is excellent in killing effect on the cells persistently infected with HIV and high in safety for the normal cells, thus leading to completion of the present invention.